Abstract Dysfunction in antigen (Ag) presentation in mucosal tissues contributes to infection, cancer, and immune disorders such as inflammatory bowel disease (IBD). The neonatal Fc receptor (FcRn) and the Fc gamma receptors (Fc?R) may be closely linked in the pathogenesis of these diseases, because they play closely complementary roles in directing how immune cells, especially dendritic cells (DC), process and respond to IgG-complexed Ag (IgG IC). Studies have shown that FcRn begins directing the immune response to IgG IC only after IgG IC have been delivered to acidic endosomes, deep inside the cell, because FcRn only interacts with IgG IC in acidic conditions. Fc?R, therefore, plays an important role in this process, by delivering IgG IC from outside the cell to the endosomes, where it appears to handoff IgG IC to FcRn, normally present in the endosome. Importantly, the common H131 variant of Fc?RIIa has been genetically associated with risk of developing inflammatory bowel disease (IBD) and cancer. Because FcRn appears to play a central role common to all Fc?R, it may be a common link enabling Fc?R genes to confer risk of disease to individuals possessing those genes. However, the details of how FcRn and Fc?R orchestrate the ?handoff? of IgG IC and how the downstream effects are directed by FcRn remain unknown. Discovering the details of the intimate coordination between FcRn and Fc?R could lead to the identification of new targets for developing better treatments for some infections, cancers and autoinflammatory diseases. The objectives of this application are to determine the details of FcRn-Fc?R cooperation, and outline how the IBD risk-associated Fc?RIIa contributes to IBD. My central hypothesis is that FcRn in DC regulates key immune functions through discrete signaling networks initiated by coordination with Fc?RIIa, that separately regulate cytokine signaling and cytoskeletal alterations. I propose to test this hypothesis through three Specific Aims. The first set of studies (Aim 1) will use biochemical techniques to show how FcRn and Fc?R interact or cooperate, and will seek to discover what other cellular components may be involved. The next studies (Aim 2), will investigate how FcRn induces immune signals to direct the immune response to the encountered Ag. The final set of studies (Aim 3) test an antibody that blocks FcRn in mouse models of IgG-dependent colitis (a model of IBD) to test the hypothesis that Fc?RIIa depends on FcRn to cause disease The rationale for this proposal is that elucidating the mechanisms of FcRn regulation of mucosal immune responses and cooperation with Fc?R will clarify the pathogenesis of IBD and reveal opportunities for therapeutic intervention to ameliorate inflammation. These studies are innovative and may benefit human health, because they investigate a newly discovered immune receptor interaction, seek to explain the mechanism of how Fc?RIIa confers risk of disease, and may provide new targets for developing new therapeutics for Fc?R-related diseases.